At present, many reaction vessels having a very small capacity are developed for use to amplify or detect DNA or the like. To deal with a large number of samples, it is preferred that many samples can be processed at once and that the costs are lower. Therefore, the vessel preferably has a capacity which is as small as possible.
In recent years, proposals have been made for use of a micro chamber formed on a silicon or glass wafer by a semiconductor process technique, as a micro-capacity vessel. This kind of reaction vessel with a micro capacity is formed in a silicon wafer or glass which has a diameter of about 4 inches. For example, Jan. Pat. Appln. KOKAI Publication No. 5-317030 discloses a biochemical reaction apparatus which comprises a plurality of micro chambers. This apparatus is capable of treating simultaneously samples of small amounts under various reaction conditions. However, the apparatus is not intended to make detection after completion of reactions.
Japanese Patent Application KOKAI Publications No. 11-75812 and 10-18922 each disclose a tube-like reaction vessel in which a nucleic acid probe is internally immobilized to detect DNA. To use this vessel, a sample containing single-stranded DNA labeled with a fluorescent material is added to the vessel, and subsequently, hybridization reaction is performed, thereby to detect DNA having a specific base sequence. In general, a large number of reaction vessels are integrated and arrayed in this kind of apparatus. Further, all the reaction vessels are arranged on one same plane so that optical observation can be performed advantageously. However, in this apparatus, the number of reaction vessels that can be integrated is limited. In case of arranging reaction vessels in one same plane, a problem arises in that the shape is complicated due to integration. If the shape is complicated, it is difficult to make simple detection such as scanning with use of a linear optical sensor. It may be necessary to carry out complicated image processing continuously after detection. Besides, the flow of liquid can be deteriorated with higher possibility as the shape is complicated more. As the number of bending parts increases more, clogging of the tube is caused more frequently.
On the other hand, samples before an experiment are maintained on a plate having 96 or 384 wells. As a means for transferring sample liquids from the plate to a reaction vessel, a multiple pipette is used. Therefore, the interval between sample wells is desirably set to a value defined by multiplying 9 mm, which is an interval between wells in a plate having 96 wells, by a fraction of an integer. However, an interval of 4.5 mm is maintained if it defined by multiplying 9 mm by xc2xd. Therefore, if sample-introducing holes having this interval are designed for a micro chamber, the inflow and outflow ports occupies the most part of the surface area on a silicon wafer having a diameter of about 4 inches. Consequently, it is difficult to integrate a large number of reaction vessels with a high density.
The present invention relates to an apparatus in which a large number of samples can cause reaction and optical detection can be carried out.
According to the present invention, there is provided a high-density capillary array for reaction and detection of fluid, comprising a plurality of fluid processing capillaries arranged in parallel on one same plane, the fluid processing capillaries each comprising: a reaction part for performing processing on fluid; connection parts connected to each end portion of the reaction part; and opening portions provided at ends of the connection parts, for allowing the fluid to flow into and out of the reaction part, wherein each of the fluid processing capillaries is bent at portions between the reaction part and the connection parts.
An object of the present invention is to provide a reaction apparatus comprising a greater number of reaction vessels, and particularly, a reaction apparatus in which reaction parts are arrayed at a high density in order to carry out reaction and detection advantageously. This object can be achieved by: arranging each reaction vessel to have a capillary shape; constructing a capillary array by integrating reaction parts of the vessels at a high density; and using a light-transmissible member for at least one part. In this manner, the inside of the fluid processing capillaries according to the present invention can be observed optically. During detection, the reaction parts substantially behave as detector parts. The high-density integration described above can be achieved by providing the reaction parts concentrated on the center, and by providing inflow and outflow ports for fluid at a peripheral part of the apparatus. Since the reaction parts are concentrated on the center, conditions of the reaction parts such as temperature and the like can be managed easily. Also, in case where detection is carried out in the reaction parts, the scanning range is advantageously narrow since the reaction parts are concentrated on the center. Narrowing the measurement range can repress harmful influences on optical measurement results from deformation of the apparatus. Besides, the processed shapes can be managed uniformly when manufacturing the present apparatus.
Further, according to the present invention, there is provided a high-density capillary array for reaction and detection of fluid, comprising a plurality of groups of fluid processing capillaries arranged in parallel on one same plane, the fluid processing capillaries each comprising: a reaction part for performing processing on fluid; connection parts connected to both end portions of the reaction part; and opening portions provided at ends of the connection parts, for allowing the fluid to flow into and out of the reaction part, wherein each of the groups of fluid processing capillaries is bent at least one portion, and the groups of fluid processing capillaries are arranged such that corner portions confront bent face back to back each other.
In the present invention, each of groups of capillaries is bent at least one portion of the reaction parts, and the capillaries are arranged such that the corner portions confront bent face back to back each other. It is therefore possible to array much more capillaries within a small area. Thus, a further another object of the present invention is to provide a micro reaction apparatus comprising much more reaction vessels.
If much more reaction vessels are provided in one conventional apparatus, the shape of each reaction vessel tends to be complicated. As a result of this complication, there is a possibility that fluid is insufficiently filled into the vessels. Hence, the present invention further has an object of providing a reaction apparatus in which the shape of each reaction vessel is much simpler so that samples can be let flow in and out smoothly. This object can be achieved by: constructing the capillary array with the shape of each vessel arranged to have a capillary shape; bending capillaries, which are included in the array, at least one portion; and arranging the capillaries such that the corner portions confront bent face back to back each other. For example, liquid having a high viscosity can be easily let flow in and out by adopting the shape according to the present invention.
Further another object of the present invention is to provide a reaction vessel capable of advantageously carrying out processing on a large number of samples with use of a multiple pipette. If a large number of capillaries are integrated at a high density, the inflow and outflow ports tend to concentrate in accordance with the high-density integration. Therefore, the object is achieved by providing the inflow and outflow ports at peripheral parts of the apparatus and by designing the apparatus particularly in consideration of use of a multiple pipette. Since a general-purpose multiple pipette can be used, the present invention can raise the operation efficiency. If conventional techniques are used, it is necessary to replace or wash tips of the multiple pipette when it is desired that samples should be added through inflow ports of reaction vessels from a multi-wells plate by a multiple pipette and liquid should be moved to another or the original multi-wells plate through outflow ports of the vessels after reaction. This is because different liquid enters into the tips. If the liquid which enters into the tips is changed, consecutive numbers in the column direction on the multi-wells plate are also changed. In the capillary array according to the present invention, excellent correspondence is maintained between the inflow and outflow ports, and a measure for minimizing difference in volume between the capillaries is provided. Accordingly, the present invention is advantageous for use of a multiple pipette.
The term of xe2x80x9cfluidxe2x80x9d used in the present specification means liquid and gas.
The term of xe2x80x9ccapillaryxe2x80x9d also used in the present specification means a tubular vessel which has two opening portions and comprises a reaction part, connection parts, and opening portions. The xe2x80x9creactionxe2x80x9d used herein means any reaction such as chemical or bio-chemical reaction, various detection such as optical detection or the like, and chemical or physical processing such as heating, cooling, or the like.
Additional objects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out hereinafter.